title: Effect of phosphodiesterase-5 inhibition on apoptosis and beta amyloid load in aged mice.
abstract: Age-related cognitive decline is accompanied by an increase of neuronal apoptosis and a dysregulation of neuroplasticity-related molecules such as brain-derived neurotrophic factor and neurotoxic factors including beta amyloid (Aβ) peptide. Because it has been previously demonstrated that phosphodiesterase-5 inhibitors (PDE5-Is) protect against hippocampal synaptic dysfunction and memory deficits in mouse models of Alzheimer's disease and physiological aging, we investigated the effect of a treatment with the PDE5-I, sildenafil, on cell death, pro- and antiapoptotic molecules, and Aβ production. We demonstrated that chronic intraperitoneal injection of sildenafil (3 mg/kg for 3 weeks) decreased terminal deoxyuridine triphosphate nick end labeling-positive cells in the CA1 hippocampal area of 26-30-month-old mice, downregulating the proapoptotic proteins, caspase-3 and B-cell lymphoma 2-associated X, and increasing antiapoptotic molecules such as B-cell lymphoma protein-2 and brain-derived neurotrophic factor. Also, sildenafil reverted the shifting of amyloid precursor protein processing toward Aβ42 production and the increase of the Aβ42:Aβ40 ratio in aged mice. Our data suggest that PDE5-I might be beneficial to treat age-related detrimental features in a physiological mouse model of aging.
authors.affiliation: Department of Bio-Medical Sciences, Section of Physiology, University of Catania, Catania, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Puzzo
authors.forename: Carla
authors.initials: C
authors.lastname: Loreto
authors.forename: Salvatore
authors.initials: S
authors.lastname: Giunta
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Musumeci
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Frasca
authors.forename: Maria Vittoria
authors.initials: MV
authors.lastname: Podda
authors.forename: Ottavio
authors.initials: O
authors.lastname: Arancio
authors.forename: Agostino
authors.initials: A
authors.lastname: Palmeri
mesh_terms: D000375:Aging / Q000378:metabolism* / Q000473:pathology*; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D056547:CA1 Region, Hippocampal / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000502:physiology*; D003856:Deoxyuracil Nucleotides / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007274:Injections, Intraperitoneal; D051379:Mice; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D009473:Neuronal Plasticity / Q000235:genetics; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D010766:Phosphorylation; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011687:Purines / Q000008:administration & dosage / Q000494:pharmacology; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000008:administration & dosage / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D003856:Deoxyuracil Nucleotides; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D011687:Purines; D013450:Sulfones; D051028:bcl-2-Associated X Protein; C027078:deoxyuridine triphosphate; D000068677:Sildenafil Citrate; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D053148:Caspase 3
keywords: APP processing; Aging; Apoptosis; BDNF; Bax/Bcl-2 ratio; Beta-amyloid; Caspase-3; Sildenafil